1. Field of the Invention
The present invention is directed to inhalers for the controlled inhalation of medication by a patient by self-activation. More particularly, it is directed to an inhaler which receives inhalation canisters for manual release of pressurized medication in spray form into the mouth and the inhaler is adapted to include a counting means to enhance proper self-administration of doses by patient.
The present invention generally relates to inhalation devices such as metered dose inhalers (MDIs), nebulizers, and dry powder inhalers. More particularly, the invention is directed to a dose controlled counting actuator that operates in conjunction with an inhalation device to prevent both patient under-compliance with prescribed medication dosing and patient abuse of or dependence on prescribed medication. Specifically, the invention contemplates the use of an actuator to prevent patient actuation of the inhalation device at non-prescribed intervals or at higher than prescribed doses.
2. Description of the Prior Art
Patient compliance with a doctor's instructions on prescribed medication is extremely important in the treatment of medical disorders. Although the rate of patient compliance is higher when he or she must return to the hospital or physician's office to receive the medication, most drug treatment regimens require the patient to administer the drugs at regular intervals without supervision by hospital personnel or the patient's physician or other qualified medical personnel. Obviously, the treatment of a medical disorder will be frustrated if the patient does not administer the drugs as prescribed. In the past, physicians have had to rely on the patient's self-interest in his or her own well being to assure that drugs are properly administered as scheduled.
With anti-anxiety or sedative/hypnotics, such as valium and barbiturates, it is widely recognized that there is a real possibility that the patient will abuse or become dependent on the drug. In Clinical Toxicology 8(5):495-513 (1975), it was argued that physicians should avoid the prescription of barbiturates because of the risk of dependence and the high toxicity of the drugs. Miller et al., American Family Physician v40, n4, p175(9) (October 1989), reported on the use of benzodiazepine drugs in the treatment of anxiety and particularly discussed the identification of dependence and addiction to these drugs. Bird, Northwest Medicine 69(8)533 (1970), reported on the problem of sedative overdose and suggested that sedatives should only be dispensed in small quantities and only on a restricted basis. Magnes, Applied Therapeutics (Toronto) 7:649 (1965) discussed the problems in the use of tranquilizing drugs in treating patients with psychoneuroses and demonstrated that in many patients treated with ethclorvynol an addiction develops.
Many drugs have a narrow therapeutic range and can have severe side effects. It is well recognized that controlling the dosing of these types of drugs is important in mitigating problems with side effects. Salzman, Hospital and Community Psychiatry (Washington) 33:2, 133-136 February 1982, reported that elderly patients are more susceptible to psychotropic drug toxicity, severe extrapyramidal side-effects from neuroleptics, and anticholinergic side-effects from tricyclic antidepressants. Milner, Medical Journal of Australia (Sydney) 2(3):153-155 (1969), reported that psychotropic drugs can have gastrointestinal side effects. Miller et al., American Family Physician v40, n4, p175(9) (October 1989), reported that benzodiazapine drugs pose adverse side effects to patients.
Many drugs can be extremely expensive (e.g., certain purified peptides and proteins). Controlling patient dosing of these drugs can have economic benefits.
An MDI typically comprises a canister under pressure fitted with a metering valve where the canister is filled with an aerosol formulation that includes a drug dissolved or dispersed in a propellant together with a surfactant. Nebulizers are devices which include mechanical or electronic devices (e.g., piezoelectric element) to atomize a drug suspension positioned in a containment cup. Nebulizers include an air or other gas source to deliver the atomized drug to the patient as a fine mist. Dry powder inhalers include mechanical or electronic devices to produce a fine mist from a powdered drug composition. MDIs, nebulizers, and dry powder inhalers have been used for many years to treat pulmonary disorders such as asthma. Examples of the types of drugs which have been routinely provided by these aerosolizing devices include: .beta.-agonists such as albuterol (salbutamol), isoproterenol, ephedrine, epinephrine, salmeterol, terbutaline; corticosteroids such as triamcinolone acetonide, beclomethasone diproprionate, dexamethasone, and aldosterone; allergic mediators such as cromclyn sodium; antibiotics; and anticholinergics.
Patient non-compliance with inhalation devices has been recognized as a major medical problem. In 1985, Dr. Spector reported in Spector, "Is your Asthmatic Patient Really Complying?", Annals of Allergy, 55:552-556 (1985), that patient compliance using a nebulizer to deliver lodoxamide, a cromolyn-like aerosol having a prophylactic (as opposed to immediate) bronchodilator effect, was extremely poor. In the investigation, patients were provided with a device called a Nebulizer Chronolog which contained a microswitch and timer that recorded the time of each use of the nebulizer. In addition, the patients were asked to record their use of the nebulizer in a diary. The patients were not told that the time of actuation of the nebulizer was also being automatically recorded. Over a several week study where lodaxamide was to be delivered at prescribed hourly intervals, it was determined from the automatically recorded usage data that all patients underdosed themselves. The mean rate of underusage was 48% for the study and the highest rate of underusage was 95.6%. Nevertheless, many patients did not tell the truth about their underusage in their diaries.
In a later study, Mawhinney et al., "Compliance in clinical trials of two nonbronchodilator, antiasthma medications", Annals of Allergy, 66:294-299 (1991), two groups of patients were provided with MDIs that were insertable into Nebulizer Chronolog devices (reported to be available from the ATA Corporation of Denver, Colo.). One group received either lodoxamide or placebo, while the other group received tixocortol pivalate or placebo. Even though patients were told they were being monitored, compliance was very low. Underusage was observed in a number of patients. In addition, overusage was observed in a number of patients, especially on days preceding follow up visits to the physicians office. In fact, only one patient in thirty four was found to be truly compliant.
There is a need to improve patient compliance with prescribed dosing schedules. As was reported in Nedelmann, Nervenarzt 53(1):33-38 (1982), it was reported that patient compliance with a doctor's drug prescription for psychotherapeutic drugs is only around 50%. Furthermore, Kahl et al., Public Health Reports Vol. v107, issue n1, page p37 (110) (January-February 1992) reported that overuse, underuse and inappropriate use of drugs by elderly patients are common problems. Several different solutions have been proposed for helping improve patient compliance. For example, Morris et al., Comprehensive Psychiatry 15(6):537-547 (1974), suggested that overdoses with the widely prescribed psychotherapeutic drugs may be avoided if there was a requirement of including an emetic or some other agent as a deterrent in the drugs, Witt, Dissertation Abstracts International 39(11):5321-B (1979) discusses the use of post-discharge pill count measurements, Beardsley, (Ph.D Dissertation University of Minn. 1977) reports a study that demonstrated increased compliance with a patient's increased knowledge about drugs gained by close interaction with pharmacists, and Venulet, Journal of Clinical Pharmacology and Biopharmacy (Munchen) 15(4):151-154 (1977), notes that having doctors understand the personality and sociocultural background of patients will aid in compliance. This invention is particularly directed to an improved inhalation device which aids in assuring patient compliance.
There is also a need for an inhalation device which can provide some assurance that a patient is not circumventing a dosing schedule by not inhaling medication. Mawhinney et al., Annals of Allergy, 66:294-299 (1991), points out that the Nebulizer Chronolog has no mechanism to determine whether a patient has activated the MDI without inhaling medication or how often they might have done so. Mawhinney et al. particularly note that Fox, Bull Int. Union Against Tuberculosis 32:307-331 (1961), reports that the self-administration of medicaments was studied in depth and it was particularly noted that home health visitors frequently found supplies of unused medications in a patient's home, despite finding a correct number of pills in the containers presented to the health investigators. Hence, there is a tendency of some patient's to "cheat" on dosing schedules. Preventing a patient's ability to "cheat" would help ensure compliance with prescribed dosing schedules.
As a result of suggestions made by one of the inventors, in consultations at Ft. Detrick, Md., scientists at the U.S. Army Medical Research Institute of Infectious Diseases in 1975 adapted a Collison nebulizer to deliver a continuous flow of small particle aerosols to mice infected with influenza virus. This system was described by Young and his associates in 1977 (Young, H. W., Dominik, J. W., Walker, J. S., Larson, E. W. Continuous aerosol therapy system using a modified Collison nebulizer. J Clin Microb 1977; 5(2):131-136). Several papers were published subsequently dealing with the use of this technology to treat influenza infections in mice with rimantadine (Stephen, E. L., Dominik, J. W., Moe, J. B., Spertzel, R. O., Walker, J. S. Treatment of influenza infection of mice by using rimantadine hydrochloride by the aerosol and intraperitoneal routes. Antimicrob Ag Chemother 1975; 8(2):154-158, amantadine and ribavirin Walker, J. S., Stephen, E. L., Spertzel, R. O. Small particle aerosols of antiviral compounds in treatment of type A influenza pneumonia in mice. J Infect Dis 1976; 133:A140-A144). Another study compared the effect of ribavirin given by the intraperitoneal and aerosol routes in influenza infections in mice (Stephen, E. L., Dominik, J. W., Moe, J. B., Walker, J. S. Therapeutic effects of ribavirin given by the intraperitoneal or aerosol route against influenza virus infections in mice. Antimicrob Ag Chemother 1976; 10(3):549-554) and on the physiological alterations in mice with influenza, untreated and treated with ribavirin aerosol (Arensman, J. B., Dominik, J. W., Hilmas, D. E. Effects of small particle aerosols of rimantadine and ribavirin on arterial blood pH and gas tensions and lung water content of A2 influenza-infected mice. Antimicrob Ag Chemother 1977; 12(1):40-46). Berendt and associates made further studies of treatment of influenza in mice with ribavirin aerosol (Berendt, R. F., Walker, J. S., Dominik, J. W., Stephen, E. L. Response of influenza virus-infected mice to selected doses of ribavirin administered intraperitoneally or by aerosol. Antimicrob Ag Chemother 1977; 11(6):1069-1070).
Based on the foregoing work, technology was adapted for human use by the inventor in his laboratory (Wilson, S. Z., Knight, V., Moore, R., and Larson, E. W. Amantadine small particle aerosol: generation and delivery to man. Proc Sol Exper Biol Med 1979; 161:350-354). Studies in mice in the inventor's laboratory confirmed the earlier results and, in addition, showed that a substantial therapeutic effect was demonstrable when treatment was delayed for as long as five days after inoculation (Knight, V., Wilson, S. Z., Wyde, P. R., Drake, S., Couch, R. B., Galegov, G. A., Novokhatsky, A. S. Small particle aerosols of amantadine and ribavirin in the treatment of influenza. In Ribavirin: A Broad Spectrum Antiviral Agent. Smith, R. A. and Kirkpatrick, W. (ed), Academic Press, Inc., New York 1980; pp. 129-145; Wilson, S. Z., Knight, V., Wyde, P. R., Drake, S., Couch, R. B. Amantadine and ribavirin aerosol treatment of influenza A and B infection in mice. Antimicrob Ag Chemother 1980; 17(4):642-648; Knight, V., Bloom, K., Wilson, S. Z., Wilson, R. K. Amantadine aerosol in humans. Antimicrob Ag Chemother 1979; 16 (4):572-578). These studies additionally show that a combination of ribavirin and amantadine increase the effectiveness of therapy.
While the animal studies, in this case mice, demonstrated the efficacy of aerosol treatment, and encouraged human trial, the human trials were done with the realization that therapeutic effect, tolerance and toxicity may be quite different in man and animals. For example, in Wilson, et al, 1979, Amantadine Small Particle Aerosol: Generation and Delivery to Man, supra, in using the arbitrary criteria for retention of aerosol in mice and man, the estimated dosages in mice were approximate four-fold those in man when similar exposure periods were employed. Up until the present development, there was no determination made of the aerosol concentration of the drug which provided an effective, tolerant and nontoxic concentration for man. In addition, most available nebulizers provide coarse particles, that is particles having a mean diameter of 10 microns and over which are too coarse to penetrate effectively into the lungs.
While the small particle or nebulizer apparatus described and used in Wilson, et al, 1979, generated small particles and produced the results there set forth, it had the following disadvantages, (1) the valve from the bag to the mask would clog with precipitated drugs from the aerosol and the mere insertion of mechanical valves, however efficient, inevitably creates some obstruction that in some degree obstructs the flow of aerosol to the patient; (2) the air exhaled by the patient is forced into the aerosol stream flowing to the patient and the patient then inhales his own exhaled air from which the drug had been removed; and (3) the efficiency of the apparatus needed to be improved to provide a higher concentration of drug per liter of aerosol.
U.S. Pat. No. 4,211,711 is directed to ribavirin, and the small particle aerosol or nebulizer apparatus of this invention is particularly well suited to deliver small particle ribavirin for treatment of the respiratory tract including the lungs.
The most pertinent prior art relating to the present invention known to the applicant is the prior art set forth above in this section of the Background of the Invention.
In recent years, changes in living style have encouraged increasing numbers of homes to adopt the practice of spreading carpets directly on concrete or wooden floors, or first placing mats or highly hygroscopic tatamis (straw matting used as a floor covering) directly on such floors and then placing carpets on top of the mats or the tatamis. These floor coverings have fostered the growth of various species of acaroid mites, house dust mites, and cheyletidaes, which not only displease the inhabitants of the house, but also expose them to such diseases as allergic asthma and tetter. Wool carpets and mouton coverings become infested with case-bearing clothes moths and carpet beetles which live on animal hair. The larvae of these harmful insects hide deep in the roots of the carpet yarns, eat into such roots at random, and spoil the carpet's value.
The gradual elevation of living standards has given rise to frequent use of numerous types of agents for external application such as, for example, furniture cleaners, antistatic agents for clothes, phonographic records, and plastic articles, waterproofing agents and stain removers for clothes, softening agents and polishing agents for leather articles, fungistatic agents and deodorants for clothes and leather articles, flameretardants for curtains and wall papers, cleaners and defrosters for glass articles, rust-proofing lubricants for sliding doors, lubricants for various sliding surfaces, bactericidal deodorants for sick rooms and sick beds, repellents and insecticides for toy animals, agents for hair care, repellents and insecticides for stuffed animals, and detergents for carpets.
Heretofore, hand pumps and aerosol sprays have prevailed as the means for the application of such agents to carpets and other floor coverings. They, however, entail the following problems:
(1) These devices do not enable their contents, such as insecticides, to reach the roots of the carpet yarns. The contents thus applied, though effective from the preventive point of view, fail to produce the anticipated effects upon mites and harmful insects already inhabiting the carpet.
(2) Since the devices disperse their contents in the surrounding spaces, they may expose their users to the danger of inhaling noxious substances drifting in the air and suffering from loss of health.
(3) Since the devices inevitably permit dispersion of their contents during the course of application, part of the released agents which fail to land on the surfaces under treatment adhere to nearby furniture and fittings to stain their surfaces and smear their surroundings.
(4) When objects under treatment are not smooth flat surfaces, as in articles of felt, for example, the devices are incapable of enabling their contents to reach the roots of raised strings.
As one approach to the solution of these problems, furniture cleaners have been devised which have doughnut-shaped brush caps and sponge adapters fitted around injection spray nozzles. With these devices, users are allowed barely to spray their contents on the surfaces of given objects and then spread the contents deposited on the surfaces with the aid of brushes or sponges separately provided near the spray nozzles of the containers. Thus, these devices are still incapable of overcoming the problems (1)-(4) enumerated above. The surfaces effectively treated by these devices are limited in area and the released agents cannot be spread uniformly.
In recent years, changes in living style have encouraged increasing numbers of homes to adopt the practice of spreading carpets directly on concrete or wooden floors, or first placing mats or highly hygroscopic tatamis (straw matting used as a floor covering) directly on such floors and then placing carpets on top of the mats or the tatamis. These floor coverings have fostered the growth of various species of acaroid mites, house dust mites, and cheyletidaes, which not only displease the inhabitants of the house, but also expose them to such diseases as allergic asthma and tetter. Wool carpets and mouton coverings become infested with case-bearing clothes moths and carpet beetles which live on animal hair. The larvae of these harmful insects hide deep in the roots of the carpet yarns, eat into such roots at random, and spoil the carpets' value.
The gradual elevation of living standards has given rise to frequent use of numerous types of agents for external application such as, for example, furniture cleaners, antistatic agents for clothes, phonographic records, and plastic articles, waterproofing agents and stain removers for clothes, softening agents and polishing agents for leather articles, fungistatic agents and deodorants for clothes and leather articles, flame-retardants for curtains and wall papers, cleaners and defrosters for glass articles, rust-proofing lubricants for sliding doors, lubricants for various sliding surfaces, bactericidal deodorants for sick rooms and sick beds, repellents and insecticides for toy animals, agents for hair care, repellents and insecticides for stuffed animals, and detergents for carpets.
Heretofore, hand pumps and aerosol sprays have prevailed as the means for the application of such agents to carpets and other floor coverings. They, however, entail the following problems:
(1) These devices do not enable their contents, such as insecticides, to reach the roots of the carpet yarns. The contents thus applied, though effective from the preventive point of view, fail to produce the anticipated effects upon mites and harmful insects already inhabiting the carpet.
(2) Since the devices disperse their contents in the surrounding spaces, they may expose their users to the danger of inhaling noxious substances drifting in the air and suffering from loss of health.
(3) Since the devices inevitably permit dispersion of their contents during the course of application, part of the released agents which fail to land on the surfaces under treatment adhere to nearby furniture and fittings to stain their surfaces and smear their surroundings.
(4) When objects under treatment are not smooth flat surfaces, as in articles of felt, for example, the devices are incapable of enabling their contents to reach the roots of raised strings.
As one approach to the solution of these problems, furniture cleaners have been devised which have doughnut-shaped brush caps and sponge adapters fitted around injection spray nozzles. With these devices, users are allowed barely to spray their contents on the surfaces of given objects and then spread the contents deposited on the surfaces with the aid of brushes or sponges separately provided near the spray nozzles of the containers. Thus, these devices are sill incapable of overcoming the problems (1)-(4) enumerated above. The surfaces effectively treated by these devices are limited in area and the released agents cannot be spread uniformly.
The use of inhalers is well known and the art has developed over the past twenty years to cover many versions of the basic concept of a "pumping" type medication applicator. The device is not truly pumped although a pumping like cycle is utilized. The medication is repeatedly released from a disposable canister, e.g. by depressions by the patient to create repeated sprays or inhalations as needed.
U.S. Pat. No. 3,361,306 to W. M. Grim illustrates a typical inhaler where a canister of medication is inserted into the back end of a device and the spray nozzle of the canister sits in a spray-directing member to shoot spray out of the front (mouth) end of the device when the canister is pressed down by a user.
U.S. Pat. No. 3,183,907 describes an inhaler in which a button on its underside is pushed by the user to release a controlled or metered amount of spray from a medication canister held in the top or back end of the inhaler.
U.S. Pat. No. 4,817,822 to Paul Rand et al describes an inhaler device which includes counting means for indicating the relative emptiness of a container or the number of doses dispensed. However, this inhaler counting mechanism is attached to the medicine container as well as the inhaler, such as by a retaining ring or retaining cap and is preferably not removed from the container.
Notwithstanding the prior art, the use of counters for an exact count of sprays per application, e.g. five sprays or six sprays each time the device is used, is not taught nor rendered obvious by the prior art, nor is the use of a timer to enable the user to control the elapsed time, e.g. 60 seconds, between each spray of a multispray application, as in the present invention.
Numerous innovations for an aerosol and non-aerosol spray counter have been provided in the prior art that are described as follows. Even though these innovations may be suitable for the specific individual purposes to which they address, they differ from the present invention as hereinafter contrasted.